Previous research had shown that there is a preferential loss of the myelin-associated glycoprotein (MAG) from the periphery of multiple sclerosis (MS) plaques in comparison to other myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP) and 2', 3'-cyclic nucleotide 3,-phosphodiesterase (CNP). Furthermore, much of the remaining MAG in affected MS tissues is in the form of a soluble 90 kD proteolytic cleavage product of MAG lacking its transmembrane and cytoplasmic domains. This proteolysis of MAG is catalyzed by a myelin-associated neutral protease that is activated in MS tissue. C-terminal amino acid sequencing and mass spectroscopic analysis of purified bovine and human dMAG were utilized to demonstrate that the native proteolytic site is between residues 512 (Ala) and 513 (Lys) just outside of the membrane. The amino acid sequence around the scissile bond suggests that this proteolysis is catalyzed by a cathepsin L-like cysteine protease. The presence of cathepsin L-like activity in myelin was confirmed by petidolysis experiments with known cathepsin L substrates, and experiments to characterize this myelin-related enzyme are in progress. Since in adult brain, MAG is localized exclusively in the periaxonal membranes of myelinating oligodendroctyes, the selective quantitative and qualitative alterations of MAG in MS plaques indicate that there is damage to the periaxonal membranes in this disease. These biochemical findings, as well as some morphological observations in the literature, suggest that one aspect of the pathology in some MS lesions is a dying-back oligodendrogliopathy in which the first abnormalities occur in the most distal periaxonal oligodendroglial membranes. In most genetic hypomyelinating disorders which we have examined, the converse is true; i.e., MAG is preserved relative to the proteins of compact myelin, MBP and PLP. This is because there is a greater deficiency of compact myelin than of the associated oligodendroglial membranes in which MAG is localized. However, we recently characterized a novel neurological rat mutant in which there is also a selective loss of MAG in comparison to the proteins of compact myelin. This is the "taiep" rat which appears to have a primary defect of microtubules causing impaired transport of proteins to myelin sheaths. Since MAG is the most distally located of the myelin proteins, it is most severely affected. Although the primary defect in this inherited disorder is quite different from that in MS, these findings support the hypothesis that an oligodendroglial abnormality that impairs the cells capacity to maintain myelin causes a preferential loss of periaxonal MAG in comparison to other myelin proteins.